Device for Containing, Reacting and Measuring, and Method of Containing, Reacting and Measuring

ABSTRACT

The invention relates to a device for containing, reacting and measuring, and a method of containing, reacting and measuring, and provides a device for containing, reacting and measuring, and a method of containing, reacting and measuring which is also able to effectively and quickly perform the reaction processing, measuring and identification. The invention comprises; a transparent container section having a liquid inlet/outlet and which is able to contain a base member with various substances for detection having predetermined chemical structures fixed at respective fixed positions which are arranged in a predetermined condition, and with each of the chemical structures associated with each of the fixed positions, a drawing and discharging section which is able to draw and discharge the liquid into and from the container section via the inlet/outlet, and a measuring device which is able to receive light from the contained base member, external to the container section and in a condition associated with the fixed position.

The referenced application claims benefit to Japanese Patent ApplicationNo. 2001-034556, filed Feb. 9, 2001.

TECHNICAL FIELD

The present invention relates to a device for containing, reacting andmeasuring, and a method of containing, reacting and measuring. Theinvention relates to all manner of fields which require the handling oflow molecular weight organisms and biopolymers such as genes, immunesystems, amino acids, proteins and sugars, including for example thefields of engineering, agricultural science incorporating foodstuffs,agricultural production and seafood processing, pharmaceuticals, themedical field incorporating hygiene, health, immunity, disease andgenetics, and scientific fields such as chemistry and biology.

In particular, the present invention relates to a device for containing,reacting and measuring and a method of containing, reacting andmeasuring which is suitable for the analysis of genes includingmutational analysis, polymorphic analysis, mapping, base sequenceanalysis, and mechanism analysis.

BACKGROUND ART

Currently, when determining gene base sequences a DNA chip is used.

This DNA chip is a flat sheet comprising a semiconductor film or a slideglass on to which is spotted a minute quantity of suspensions of a largenumber of different, known oligonucleotides, with the oligonucleotidesfixed in an array pattern sequence. The DNA chip is made by using apipette apparatus in order to form a plurality of oligonucleotides onthe restricted surface thereof, minute quantities of oligonucleotidesuspensions being dispensed spot by spot on to the surface while leavinga predetermined separation between adjacent spots to prevent mixing. Byusing such a DNA chip, various assay or analysis related to genes isperformed.

For example, in determining the base sequence of an unknown target gene,conventionally the user pours a liquid with the target genetic materialsuspended therein and which is labeled with a luminescent material, ontothe DNA chip. Then after leaving for a fixed reaction time, the surplussuspension is removed by washing. Subsequently, the luminescence fromthe DNA chip is detected to thereby determine the base sequence from theposition where the luminescence is detected.

However, in order to manufacture the DNA chip, with the arrangement of alarge number of different oligonucleotides at a high density in a planeon a restricted region, not only is there the likelihood ofcross-contamination occurring due to these becoming close to each other,but also the oligonucleotides at each of the fixed positions becomes aneven smaller amount. In particular, if the oligonucleotides at each ofthe fixed positions becomes a small amount, determining the luminescenceposition is susceptible to error so that there is a problem withaccuracy. Furthermore, due to miniaturization, there is a problem inthat the encounter characteristics or reactivity of the target substanceis reduced, so that processing takes time.

Moreover, since the sample is arranged in a plane, then with higherdensities, the handling and automation thereof is even more difficult.Consequently, the manufacture of the DNA chip requires a considerableamount of effort and time, resulting in high cost. In particular, inperforming analysis, assay or determination of the structure of largeamounts of unknown target substances which contain base sequences, theanalysis, assay etc. of a large amount of DNA chips is necessary.Therefore, the present applicant in order to solve this problem hasdisclosed in patent applications (Unpublished Patent Application Nos.2000-7763, 2000-37273, 2000-77144, not yet published at the time of thisapplication), an integrated support which has one, or two or more longslender base members of for example filaments, fibers, tapes, or rods,and a variety of substances for detection of predetermined chemicalstructures which are lined up and fixed along the longitudinal directionof the base member, the base member being rolled, laminated or arrangedin a line, so that the fixed locations of each type of substance fordetection is associated with the chemical structure thereof.

However, even though the manufacture of such an integrated carrier issimplified and the cost reduced, there is a problem in that if reaction,measuring and identification using such an integrated carrier cannotalso be performed efficiently and quickly, the advantage of thisintegrated carrier cannot be sufficiently realized.

Therefore, the present invention aims to resolve the problems outlinedabove, with a first object of providing a device for containing,reacting and measuring and a method of containing, reacting andmeasuring, which is able to effectively and quickly perform reaction,measuring and identification not only for the aforementioned carrier butalso for the DNA chip.

A second object of the present invention is to provide a device forcontaining, reacting and measuring and a method of containing, reactingand measuring, which can consistently and automatically performreaction, measuring, and identification of a target substance.

A third object of the present invention is to provide an easily operateddevice for containing, reacting and measuring and a method ofcontaining, reacting and measuring which can perform reaction,measuring, and identification using a minute amount of liquid in whichis suspended a labeled target substance.

A fourth object of the present invention is to provide a highly reliabledevice for containing, reacting and measuring, and a method ofcontaining, reacting and measuring which can perform accurateidentification of a target substance.

A fifth object of the present invention is to provide an integratedcarrier where reaction, measuring and identification is furthersimplified.

DISCLOSURE OF THE INVENTION

In order to solve the above technical problems, a first aspect of theinvention is an integrated carrier having; a base member of a long andslender shape such as a filament, a braid, or tape, with varioussubstances for detection having predetermined chemical structures fixedthereto so as to be lined up along a longitudinal direction thereof witheach of the chemical structures associated with their fixed positions,and a carrier with the base member rolled therearound with each of thefixed positions exposed outwards.

Here ubstance for detection is an already known substance to be detectedin order to determine a structure of a target substance, or to conductvarious assays or analyses, and includes genetic material such asoligonucleotides, biopolymers such as proteins, amino acids and sugars,microorganisms such as low molecular weight organisms or bacteria andviruses, and living systems such as cells.

Genetic material includes nucleic acid (polynucleotide) and itsdecomposition products oligonucleotides, nucleotides and so forth. Here,ase member is formed from a flexible material or a non flexiblematerial. This material may be for example an organic material such aspolyethylene, polystyrene, polypropylene, urethane, an inorganicmaterial such as glass fiber, ceramics, metal, or a material whereorganic and inorganic materials are combined such as where fine ceramicsparticles are spread all over a film or tape of an organic material.Furthermore the base member, may be formed, at least in each fixedposition, from various types of porous material, foam material, fibrousmaterial, or irregular surface material.

“Associating” preferably involves for example relating to positions on alayer forming face (integrated face) constituting a layered structureproduced by rolling the base member. “The base member is rolled on thesurface so that the fixed positions are exposed to the outside”, is sothat measurement can be made from outside of the container section.Consequently, a normal situation where the base member is rolled on thecarrier in only one layer in for example a cylindrical shape ispreferably.

Furthermore, the fixed positions are provided at the layer forming faceside of the base member. “Chemical structure” for example in the casewhere the substance for detection is a genetic material, is a basesequence. Regarding “rolled base member”, preferably the base member isunited and held by for example positioning the edges of the base memberin a space provided on the carrier and fixing by frictional force.

Furthermore, regarding the integrated member, when this is contained ina container section described later, preferably this has a constructionsuch that a space is formed with the inner wall of the container sectionso that liquid can flow smoothly therethrough. As a result, when theliquid is drawn, the liquid can be reliably contacted with the substancefor detection, and when the liquid is discharged, the liquid can passsmoothly between the integrated carrier and the inner wall, leaving noresidual liquid.

Such a construction is preferably realized by providing on the carrier(for example cylindrical or. prismatic shape) about which the basemember is rolled, a protective portion for preventing contact of thebase member with the inner wall of the container (also including a laterdescribed container section) for containing the integrated carrier. Theprotective portion is preferably one where a protruding portion having aheight exceeding the thickness of the rolled base member and with a tipthereof for contact with the container inner wall, is provided forexample on a suitable part (for example opposite rim portions, oppositeend portions etc.) of the carrier (for example cylindrical or prismaticshape), protruding from the surface of the carrier (for example in theradial direction).

Moreover, preferably the contact point of the protective portion withthe container inner wall is formed so as to have a minimal area. This isbecause if the area of the contact point is large, the amount ofresidual liquid is likely to increase. The shape of the protectiveportion is formed so that flow of liquid inside the container portiondoes not become impossible due to the presence of the protectiveportion. This situation is prevented for example by providing cutouts inan annularly formed protruding portion, or by providing a pin-likeprotruding portion. By means of this protective portion, the positioningof the integrated carrier inside the container portion can also beperformed.

Furthermore, in the case where minute quantities of liquid are handled,the carrier is preferably formed as a solid. Moreover, preferably thespacing between the base member and the inner wall of the container isas small as possible. On the other hand, in the case of handlingrelatively large quantities of liquid, the carrier is preferably formedfrom a hollow and/or porous member.

According to the first aspect of the invention, since the base member isrolled so that each of the fixed positions of the base member areexposed to the outside, measuring or detection of the labels for thelabeled fixed positions can be performed easily and accurately fromoutside. Consequently, if this integrated carrier is used, then at thetime of performing reaction as well as measurement, handling issimplified, and consistent processing can be performed.

A second aspect of the invention is device for containing, reacting andmeasuring wherein in the first aspect of the invention this has; atransparent container section having a liquid inlet/outlet and which isable to contain a base member with various substances for detectionhaving predetermined chemical structures fixed at respective fixedpositions which are arranged in a predetermined condition, and with eachof the chemical structures associated with each of the fixed positions,a drawing and discharging section which is able to draw and dischargethe liquid into and from the container section via the inlet/outlet, anda measuring device which is able to receive light from the containedbase member, external to the container section and in a conditionassociated with the fixed position.

Since the container section has a liquid inlet/outlet, the base memberas well as liquid can be contained in the container section. As aresult, reaction between the substance for detection of the base memberand the target substance contained in the liquid is possible inside thecontainer section. The container section has a container opening forcontaining the base member. This container opening may also be used forexample for connection to the drawing and discharging section.

Here the base member need not necessarily be a long and slender shape.Moreover, a long and slender base member which is rolled around theintegrated carrier is also possible. Furthermore, this may be forexample a planar DNA chip. “Predetermined condition” is the conditionwhere each of the fixed positions are exposed to the outside. Forexample, in the case where the base member is long and slender, this isthe condition where each fixed position is arranged in a line along thelength of the base member, while in the case where the base member isplanar, this is the condition where each fixed position is arranged inmatrix form.

Furthermore, the shape or size of the container section may be made ashape or size close to the shape or size of the base member (or theintegrated carrier), based on the shape or size of the base member (orintegrated carrier), so that the space between the container inner walland the base member is made narrow, enabling small quantities of liquidto be handled.

According to the second aspect of the invention, reaction or washing canbe performed with the same or a different liquid by drawing ordischarging the necessary liquid into or from the container section withthe base member contained in the container section, and in thiscondition measurement can also be performed. Consequently, processessuch as reaction, measurement and the like can be performed efficientlyand consistently, by a quick and a simple operation. Furthermore, sincethe various processes can be performed with the base member contained inthe container section, cross-contamination is prevented so thatreliability is high. Moreover, by determining the shape or size of thecontainer section based on the shape or size of the base member,processing can also be performed with minute quantities of liquid.

A third aspect of the invention is a device for containing, reacting andmeasuring, wherein in the second aspect of the invention, the measuringdevice has a light receiving section for receiving light from the basemember, and a scanning section for relatively moving the light receivingsection and the container section and scanning each fixed position ofthe base member. The scanning section may move the light receivingsection, or may move the container section.

According to the third aspect of the invention, by scanning the basemember, light from the base member can be received without leakage, andhence reliability of the measurement results is high.

A fourth aspect of the invention is a device for containing, reactingand measuring wherein in the second aspect of the invention, thecontainer section is removably mounted on a nozzle section provided inthe drawing and discharging section. According to the fourth aspect ofthe invention, since the container section for contacting the liquidwith the base member is removably mounted, then by replacing containersections, cross-contamination can be reliably prevented. Furthermore, byproviding a magnetic force device external to the container section, orby replacing the container section with a pipette section provided witha magnetic force device which can perform separation by attachingmagnetic particles to the inner wall, then this can be used in commonwith a device which uses magnetic particles, and hence many kinds ofprocessing can be performed even more efficiently and consistently.

A fifth aspect of the invention is a device for containing, reacting andmeasuring wherein in the second aspect of the invention, this furtherhas a moving section which is capable of relatively moving theinlet/outlet and a processing area where externally provided containersor the like are mounted. According to the fifth aspect of the invention,by providing the moving section which relatively moves the inlet/outletof the container section and the processing area, processing can beautomatically and consistently performed by moving the base member withthe base member contained in the container section.

A sixth aspect of the invention is a device for containing, reacting andmeasuring wherein in the second aspect of the invention, this furtherhas an identification section for performing identification of thetarget substance based on an identification pattern obtained by scanningwith the measuring device an area containing all fixed positions of thebase member which have been formed by combining labeled targetsubstances with substances for detection. According to the sixth aspectof the invention, an effect the same as for the third aspect of theinvention is demonstrated.

A seventh aspect of the invention is a device for containing, reactingand measuring wherein in the second aspect of the invention, the basemember is formed in a long and slender shape such as a filament shape, abraid shape, or a tape shape, and the substances for detection are linedup and fixed along a longitudinal direction thereof, and in the casewhere the base member is contained in a linearly extended condition, thecontainer section is a slender tube, and the base member is containedwith the longitudinal direction thereof along the axial direction of theslender tube, and the size and shape of the slender tube is determinedbased on the size and shape of the base member, and the measuring devicemeasures by scanning along the axial direction of the slender tube.According to the seventh embodiment, since the base member is containedin an extended condition, specifying of each fixed position is simpleand accurate.

An eighth aspect of the invention is a device for containing, reactingand measuring wherein in the second aspect of the invention, the basemember is formed in a long and slender shape such as a filament shape, abraid shape, or a tape shape, with various substances for detectionhaving predetermined chemical structures lined up and fixed along thelongitudinal direction, with each chemical structure associated with thefixed positions thereof, and in the case Where the base member forms anintegrated carrier rolled on the surface of the carrier with therespective fixed positions exposed outward, the container sectioncomprises a large diameter section for containing the integrated carrierand a small diameter section having an inlet/outlet at a tip end andcapable of insertion into an external container, and the drawing anddischarging section draws and discharges the liquid into and from thelarge diameter section via the inlet/outlet, and the size and shape ofthe container section is determined based on the size and shape of theintegrated carrier, and the measuring device receives light from thebase member external to the large diameter section. According to theeighth aspect of the invention, by determining the size and shape of thecontainer section based on the size and shape of the integrated carrier,and making the space between the integrated carrier and the inside wallof the container section narrow, processing such as reaction can beperformed even with a small quantity of liquid, thus simplifyinghandling. Furthermore, according to this aspect of the invention, sincethe base member is integrated and contained as an integrated carrier,measurement can be performed in relation to numerous fixed positions,and hence analysis of complicated structures can also be efficientlyperformed.

A ninth aspect of the invention is a device for containing, reacting andmeasuring wherein in the third aspect of the invention, the lightreceiving section of the measuring device is provided inside a lightshielding box, and the light shielding box has a box body, and a coverprovided so as to cover an opening of the box body, and has an openingprovided in the cover to allow the container section to passtherethrough in order to insert the container section into the box body,and a closure device which covers the opening to form a closure spacewith the container section inserted into the box body. As well as thelight receiving section, the illumination section may also be providedinside the light shielding box. According to the ninth aspect of theinvention, since light reception is performed inside the light shieldingbox, noise of light from outside is shut off, and light does not leak tothe outside. Hence there are no adverse effects on other measurements,enabling measurements of high reliability to be performed, and since aplurality of measurements can be performed concurrently in an integratedcondition, the efficiency is even higher.

A tenth aspect of the invention is a device for containing, reacting andmeasuring wherein in the eighth aspect of the invention, the integratedcarrier on which the base member is rolled, is contained in a conditionwith the rolled base member positioned so as not to come in contact withan internal surface of the container section.

To achieve this, for example, the abovementioned protective section maybe provided on the integrated carrier.

According to the tenth aspect of the invention, the base member ispositioned so as not to come in contact with the internal surface of thecontainer section. Consequently, sufficient contact is possible betweenthe base member and the liquid, and when discharging liquid, a situationwhere liquid remains in the space between the base member is prevented.Moreover since the base member is positioned, reliable measurement canbe performed.

An eleventh aspect of the invention is a method of containing, reactingand measuring having: a containing step for containing in a transparentcontainer, a base member of a long and slender shape such as a filament,a braid, or tape, with various substances for detection havingpredetermined chemical structures fixed thereto along a longitudinaldirection with each of the chemical structures associated with theirfixed positions; a reaction step for drawing a liquid suspending alabeled target substance to inside the container section and immersingthe base member in the liquid to react the target substance with thesubstance for detection; a measurement preparation step for removing theliquid and any target substance which has not contributed to thereaction; and a measurement step for measuring light from the basemember contained in the container section. emoval in the easurementpreparation step is performed for example by washing using a washingsolution. Washing is more effectively performed by repeated drawing anddischarging of the washing solution or by agitating. According to theeleventh aspect of the invention, effects the same as those describedfor the second aspect of the invention are demonstrated.

A twelfth aspect of the invention is a method of containing, reactingand measuring wherein in the eleventh aspect of the invention, themeasurement step scans all fixed positions of the base member byrelatively moving the container section or a light receiving position.According to the twelfth aspect of the invention, effects the same asthose described for the third aspect of the invention are demonstrated.

A thirteenth aspect of the invention is a method of containing, reactingand measuring wherein in the eleventh aspect of the invention, in themeasurement preparation step there is included a step for drawingmeasurement liquid after removing target substances which have notcontributed to reaction and liquid suspending these, and the measurementstep measures in a condition with the base member immersed in themeasurement liquid. Here for the easurement liquid it is preferable touse for example distilled water, or a liquid which has a refractiveindex close to the refractive index of the material constituting thecontainer section. According to the thirteenth aspect of the invention,instead of removing the target substance which has not contributed tothe reaction and the liquid in which this is suspended, the measurementliquid is drawn so as to immerse the base member. Consequently, byfilling a liquid having for example a predetermined refractive indexclose to the refractive index of the material constituting the containersection, between the container section and the base member, reflectionor refraction or distortion produced at the interface between thecontainer section and air can be prevented, thus giving clarity andenabling accurate measurement to be performed.

A fourteenth aspect of the invention is a method of containing, reactingand measuring wherein in the eleventh aspect of the invention, in thereaction step, the container section is shaken, or drawing anddischarging is repeated. According to the fourteenth aspect of theinvention, by shaking the container section and repeating the drawingand discharging, the encounter characteristic between the targetsubstance suspended in the liquid and the substance for detection of thebase member can be increased, and reaction promoted.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a device for containing, reacting andmeasuring according to a first embodiment of the present invention.

FIG. 2 is a schematic diagram of a device for containing, reacting andmeasuring according to a second embodiment of the present invention.

FIG. 3 is a schematic diagram of a device for containing, reacting andmeasuring according to a third and fourth embodiment of the presentinvention.

FIG. 4 is a diagram showing an example of an identification pattern of adevice for containing, reacting and measuring according to the third andfourth embodiments of the present invention.

FIG. 5 is a schematic diagram of a device for containing, reacting andmeasuring according to a fifth embodiment of the present invention.

FIG. 6 is a schematic diagram of a device for containing, reacting andmeasuring according to a sixth embodiment of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

A description is given of a minute object identification device and aminute object identification method according to embodiments of thepresent invention, based on the drawings. The description of theembodiments is not to be interpreted as limiting the present inventionunless particularly specified.

FIG. 1( a) schematically shows a device for containing, reacting andmeasuring 10 according to a first embodiment.

The device for containing, reacting and measuring 10 according to thisembodiment has a transparent slender tube 11 serving as the containersection and having a liquid inlet 12, a pump 13 connected to the slendertube 11 and serving as a drawing and discharging section for drawing anddischarging liquid into and from the slender tube 11, and a measuringdevice 14. Inside the slender tube 11 it is possible to contain aliquid, and a base member 15 immersed in the liquid.

The base member 15 is formed in a long and slender shape, and detectionsubstances such as for example oligonucleotides having already knownvarious base sequences are arranged so as to be lined up along thelongitudinal direction thereof. The base member 15 is contained insidethe slender tube 11 in an extended and secured condition so as to adhereto the slender tube 11. Here, reference symbol 16 shows where labeledtarget substances bond to the detection substance to thereby label fixedpositions thereof. By analyzing these labeled fixed positions, theunknown chemical structure of the target substance can be determined.

The pump 13 has a tube 17 made from a resilient body and communicatedwith the slender tube 11, a pressing section 18 for pressing andcontracting the tube 17, and a switching valve (not shown in thefigure). The pump 13 draws and discharges into and from the slender tube11, liquid 20 contained in a container 19 provided external to thedevice for containing, reacting and measuring 10. In the liquid 20 issuspended a target substance which has been labeled by a fluorescentsubstance or the like (not shown in the figure).

The measuring device 14 is a device for shining an excitation light beamfor exciting the fluorescent substance, and receiving the producedfluorescence. A scanning section (not shown in the figure) which ismoved for scanning, is provided along the slender tube 11.

The shape and size of the slender tube 11 is determined based on theshape and size of the base member 15, and is preferably a size and shapesuch that the base member 15 can be easily contained inside the slendertube 11 with a margin, and so that a gap produced between the inner wallof the slender tube 11 and the surface of the base member 15 is small tothe extent that the base member 15 is easily wetted with a small amountof liquid. As shown in FIG. 1( b), in order to satisfy this condition,the size of the diameter of the slender tube 11 is suitablyapproximately two times the size of the width or the diameter of thebase member 15, and for example in the case where the diameter of thebase member 15 is approximately 0.1 mm, then preferably the diameter ofthe slender tube 11 is for example approximately 0.2 mm.

Next, FIG. 2 shows a device for containing, reacting and measuringaccording to a second embodiment.

FIG. 2( a) shows a core 21 serving as a rod shape or cylindrical shapecarrier for carrying the aforementioned base member 15 rolled around thesurface thereof. FIG. 2( b) shows an integrated carrier 22 with thebeforementioned base member 15 rolled. Here the diameter of the core 21is for example from approximately 2 to 4 mm, while the thickness of thebase member 15 is from approximately 0.05 mm to 0.2 mm, and the lengthof the base member 15 is for example from approximately 500 mm to 3000mm. FIG. 2( c) illustrates a device for containing, reacting andmeasuring 23, and a method of containing, reacting and measuringaccording to the second embodiment.

The device for containing, reacting and measuring 23 has a pipettesection 24 serving as the container section, a drawing and dischargingsection 25 for drawing and discharging into and from the pipette section24, and a measuring device 26 provided external to the pipette section24. In the drawing and discharging section 25 is provided a cylinder 27,and a nozzle section 28 communicated with the cylinder 27 through apipe.

The pipette section 24 has a mounting section 29 removably mounted onthe nozzle section 28 via an O-ring 30, a small diameter section 31having a single inlet/outlet 33 at a tip end, and which is insertableinto a container 19 external to the device for containing, reacting andmeasuring 23, and a large diameter section 32 provided between the smalldiameter section 31 and the mounting section 29 and having a diameterlarger than that of the small diameter section 31 for containing theintegrated carrier 22. The opening of the mounting section 29constitutes a container opening for insertion and accommodation of theintegrated carrier 22.

The shape and size of the large diameter section 32 is determined by theshape and size of the integrated carrier 22. The size and shape of thelarge diameter section 32 is a size where the integrated carrier 22 canbe easily contained inside the large diameter section 32 with a margin,and is preferably a size and shape so that a gap produced between theinner wall of the large diameter section 32 and the surface of the basemember 15 of the integrated carrier 22 is small to the extent that thebase member 15 is easily wetted with a small amount of liquid but doesnot adhere to the inner wall of the large diameter section 32. Here theamount of liquid is for example approximately 100 m liters.

The drawing and discharging section 25 is for drawing and dischargingthe liquid 20 into and from the large diameter section 32 via theinlet/outlet 33. Furthermore, with this embodiment, while not shown inthe figure, this has a moving mechanism capable of relatively moving theinlet/outlet 33 between externally provided containers 19, 35 and 37.

Moreover, a measuring device 26 is a device which uses for example anoptical fiber for irradiating excitation light and receiving thefluorescent, being a movable device which can be scanned in the verticaldirection external to the large diameter section 32 of the pipettesection 24, and rotated through 360 degrees around the large diametersection 32.

In the device for containing, reacting and measuring 23 according tothis embodiment, the pipette section 24 is removably mounted on thenozzle section 28. Consequently, as well as the case of replacing thepipette section with another pipette section of the same constructionwhich is mountable on the nozzle section 28, a pipette with a magneticforce device provided on the outside to thereby exert a magnetic fieldso that magnetic particles are adhered to the inner wall and can thus beseparated, may also be removeably mounted.

Since by so doing, the magnetic particles can be separated, it ispossible to consistently perform processing for an even wider range alsoincluding for example extraction and separation of genetic material.Consequently, according to this embodiment, by using in common the samedrawing and discharging section, various types of processing usingmagnetic particles, and various types of processing using base memberscan be consistently and automatically performed.

Next is a description based on FIG. 2, of a method for determining basesequences for analysis of the target substance, using the device forcontaining, reacting and measuring 23 according to this embodiment.

In FIG. 2( c), at first in a step S1, a liquid 20 in which is previouslysuspended a target substance comprising a DNA fragment for which anunknown base sequence is to be determined and which has been has beenlabeled with fluorescence, is placed in the container 19.

Furthermore, an integrated carrier 22 with the base member 15 withvarious already known oligonucleotides with their base sequences andeach of their fixed positions associated, rolled around the core 21, iscontained inside the large diameter section 32 of the pipette section 24serving as the container section, and after this the pipette section 24is mounted on the nozzle section 28.

In step S1, a probe solution with a predetermined reagent mixed in aliquid in which is suspended the target substance labeled with afluorescent substance or the like, is pre-heated for a few minutes atapproximately 95° C. in a constant temperature tank 34 provided with aPeltier element. Then the current direction is changed to thereby coolthe solution to for example, a normal temperature or, if necessary, atemperature different from the normal temperature, to adjust thesolution to an easily hybridized form. In determining the unknown basesequence of the DNA fragment, needless to say as a pre-requisite, inaddition to the hybridization process, a process for denaturation of theDNA fragment is necessary.

In step S2, the small diameter section 31 of the pipette section 24 ismoved to the container 19 and inserted therein. The container 19 is heldin the constant temperature tank 34 at normal temperature, or ifrequired at a temperature different from the normal temperature, andincubation and reaction is performed over a few minutes to a few hours.

In step S3, after completion of reaction, the small diameter section 31of the pipette section 24 is moved and inserted into the container 35which contains a first cleaning solution 36 at room temperature, andthis is then shaken and washed so that the excess probe solution inwhich is suspended the target substance and the like is removed.

In step S4, after the first washing, the small diameter section 31 ofthe pipette section 24 is moved and inserted into the container 37 whichcontains unused second cleaning solution 38, and this is again shakenand washed, and the remaining probe solution is removed.

In step S5, the measuring device 26 measures from outside of theintegrated carrier for which washing is completed, by scanning theperimeter of the large diameter section 32 vertically and through 360degrees therearound with the scanning section.

Next, is a description of a device for containing, reacting andmeasuring 40 according to a third embodiment, based on FIG. 3.

FIG. 3( a) schematically shows the device for containing, reacting andmeasuring 40 according to the third embodiment. This device forcontaining, reacting and measuring 40 uses another integrated carrier42. The integrated carrier 42, as shown in FIG. 3( a) has the basemember 15 rolled around a core 41 as the carrier.

As shown in FIG. 3( b), at opposite rims of the core 41 are respectivelyprovided annular protruding portions 41 a serving as the protectiveportions. By means of these protective portions, the base member 15 isbound so as not to come off from the core 41 being the carrier, andcontact between an inner wall of a pipette section 44 serving as a latermentioned container section and the base member 15 is prevented, so thatthe liquid passing the surface of the base member 15 flows smoothly, andthe integrated carrier 42 is positioned inside the container section,thus enabling reliable measurement. Consequently, the core 41 is formedin an overall spool shape.

On these annular protruding portions 41 a are provided a plurality ofcut out portions 43 so that the liquid can pass therethrough, and thecontact portions at the tip of the annular protruding portion 41 a whichcontact with the inner wall are formed in a wedge shape so that thecontact area with the inner wall is minimal. As a result, liquid residueis prevented, and the process can be smoothly performed. The height ofthe annular protruding portions 41 a is made a height exceeding thethickness of the rolled base member 15, to thereby prevent the basemember 15 from touching or adhering to the inner wall.

Furthermore, instead of the annular protruding portions 41 a, protectiveportions 142 as shown in FIG. 3( b) may be provided. With theseprotective portions 142, a plurality of radially protruding portions 142a are provided, and the height of these protruding portions 142 a is setso as to exceed the thickness of the base member 15.

The device for containing, reacting and measuring 40 which uses theintegrated carrier 42, has a pipette section 44 serving as the containersection, a drawing and discharging section (48) for performing drawingand discharging into and from the pipette section 44, and a linear lightreceiving and irradiating section 50 provided external to the pipettesection 44. Reference symbol 48 denotes a nozzle section provided in thedrawing and discharging section (48).

The linear light receiving and irradiating section 50 is attached to arod shape support member with tip sections of a large number of opticalfibers arranged in a line. Each of the fibers is connected to aphotodetector and a light source for irradiating excitation light forexciting the fluorescent substances used in the labeling. As a result,the fluorescence excited thereby can be simultaneously received.

Furthermore, the linear light receiving and irradiating section 50 maybe such that direct photodetectors are arranged in a line, and there isprovided a light source for irradiating excitation light. This linearlight receiving and irradiating section 50 is provided so as to be ableto be turned through 360 degrees around the periphery of the largediameter section 45 by means of a scanning section (not shown in thefigure). Furthermore, the mounting portion containing the pipettesection 44 may be provided so as to be able to be rotated through 360degrees around the axis of the pipette section 44. This linear lightreceiving and irradiating section 50 corresponds to the measuringdevice.

The pipette section 44 has a removably mounted large diameter section 45engaged with the nozzle section 48 via an O-ring 49, and which containsthe integrated carrier 42, and a small diameter section 46 with a tiphaving an inlet/outlet 47, which can be inserted into a containerexternal to the device for containing, reacting and measuring 40. Herethe diameter of the large diameter section 45 is for example an innerdiameter of approximately 4 mm. The opening of the large diametersection 45 constitutes the container opening for insertion andaccommodation of the integrated carrier.

Here the annular protruding portion 41 a of the integrated carrier 42 ispreferably formed in a size to contact with the inner wall of the largediameter section 45. The outside diameter of the integrated carrier 42is for example approximately 3.8 mm.

FIG. 3( c) shows a device for containing, reacting and measuring 51according to a fourth embodiment. This device for containing, reactingand measuring 51 uses an annular light receiving and irradiating section52 as the measuring device, instead of the linear light receiving andirradiating section 50 formed in the linear shape. To the annular lightreceiving and irradiating section 52 is fitted an annular support memberwith tip portions of a large number of optical fibers 53 arrangedannularly. These optical fibers 53 irradiate excitation light and at thesame time receive fluorescence.

The other ends of the optical fibers 53 are connected to a line sensor54 comprising photodetectors arranged in a line. Furthermore, the otherends of the optical fibers 53 may be connected to a planar CCD element.Moreover, this annular light receiving and irradiating section 52 isprovided so as to be moveable vertically by means of a scanning section(not shown in the figure). Moreover, an equipment part including thepipette section 44 may be provided so as to be moveable vertically bymeans of the scanning section.

FIG. 4 schematically shows one example of a measured identificationpattern 55. Here reference symbol 56 denotes positions on an image ofthe base member 15. Reference symbol 57 denotes reference points whichare labeled beforehand so as to become references for specifying fixedpositions of the base member 15. Reference symbol 58 shows fixedpositions where the labeled target substance has been combined.According to this example, the measurement results for each of thelabeled fixed positions may be processed as planar information.

Next is a description of a device for containing, reacting and measuring60 according to a fifth embodiment, based on FIG. 5. As schematicallyshown in FIGS. 5 (a) and (b), the device for containing, reacting andmeasuring 60 according to this embodiment has; a pipette section 64serving as the container section, a drawing and discharging section 65for drawing and discharging into and from the pipette section 64, and ameasuring device 66 provided external to the pipette section 64. In thedrawing and discharging section 65 is provided a cylinder 67, and anozzle section 68 communicated with the cylinder 67 through a pipe.

The pipette section 64 has a removably mounted mounting section 69engaged with the nozzle section 68 via an O-ring 70, a small diametersection 71 with a tip having an inlet/outlet 73, and which is insertableinto a container external to the device for containing, reacting andmeasuring 60, and a large diameter section 72 provided between the smalldiameter section 71 and the mounting section 69 and having a diameterlarger than that of the small diameter section 71 for containing anintegrated carrier 62.

The integrated carrier 62 is one where the base member 15 is rolledaround a core 61. At opposite ends of the core 61 are respectivelyprovided annular protruding portions 61 a serving as the protectiveportions for protecting so that the base member 15 does not to come offfrom the core 61 and the base member 15 does not contact with the innerwall, and for ensuring smooth flow of the liquid, and for positioning.The core 61 is formed overall in a spool shape, and on these annularprotruding portions 61 a are provided a plurality of cut out portions 43so that the liquid can pass therethrough.

Here the annular protruding portions 61 a of the integrated carrier 62are preferably formed in a size so as to contact with the inner wall ofthe large diameter section 72.

The drawing and discharging section 65 is for drawing and dischargingthe liquid into and from the large diameter section 72 via theinlet/outlet 73. Furthermore this embodiment, while not shown in thefigure, has a moving mechanism which can relatively move theinlet/outlet 73 between various processing areas and processingpositions such as externally provided containers, and a later describedlight shielding box 74.

With this embodiment, the measuring device 66 is provided in the lightshielding box 74. The light shielding box 74 is used for shutting offnoise of excess light generated from the exterior or from the interiorat the time of measuring the fluorescence generated by the integratedcarrier 62. The light shielding box 74 has a box body 75 provided withthe measuring device 66 and with the pipette section 64 insertedthereinside, and a cover 76 provided on an opening of the box body 75.An aperture 77 is formed in a central portion of the cover 76 forenabling insertion of the pipette section 64. Moreover, around theperiphery of the aperture 77 a double annular wall section 78 isprovided upwardly protruding so as to form an annular groovetherebetween.

On the other hand, an annular cover plate 79 for covering the aperture77 is provided so as to protrude sideways from the surroundings of theupper portion of the nozzle section 68. On a lower side of the coverplate 79 provided so as to protrude downwards, is an annular protrusion80 for insertion into the groove formed by the double annular wall 78 toform an enclosed space thereinside. Here the cover plate 79, the doubleannular wall 78 and the annular protrusion 80 correspond to a closuredevice.

Furthermore, with the device for containing, reacting and measuring 60according to this embodiment, there is provided a rotation section (notshown in the figure) serving as the scanning section, which can rotate apart containing the pipette section 64 through 360 degrees in relationto the central axis of the pipette section 64. By rotation by thisrotation section, the annular protrusion 80 slides inside the grooveformed in the double annular wall section 78. As a result, completelight shielding is achieved, and all of the fixed positions provided onthe integrated carrier 62 contained inside the large diameter section 72can be scanned and the light received without any leakage.

FIG. 5( a) shows the condition where the pipette section 64 is beingmoved downward by the moving section (not shown in the figure) in orderto insert the pipette section 64 inside the light shielding box 74,while FIG. 5( b) shows the condition where insertion of the pipettesection 64 into the light shielding box 74 has been completed, andmeasurement is being performed.

Next is a description of a device for containing, reacting and measuring81 according to a sixth embodiment, based on FIG. 6.

The device for containing, reacting and measuring 81 according to thisembodiment, as shown in FIGS. 6( a) and (b) has; a pipette section 85serving as the container section, a drawing and discharging section 86for drawing and discharging into and from the pipette section 85, and ameasuring device 87 provided external to the pipette section 85. In thedrawing and discharging section 86 is provided a cylinder 88, and anozzle section 89 communicated with the cylinder 88 through a pipe.

The pipette section 85 has a removably mounted mounting section 90engaged with the nozzle section 89 via an O-ring 91, a small diametersection 92 with a tip having an inlet/outlet 93, and which is insertablein a container 19 external to the device for containing, reacting andmeasuring 81, and a large diameter section 94 provided between the smalldiameter section 92 and the mounting section 90 and having a diameterlarger than that of the small diameter section 92 for containing anintegrated carrier 82. The opening of the large diameter section 94constitutes the container opening for insertion and accommodation of theintegrated carrier.

The integrated carrier 82 has a region 84 where this is rolled as aspiral within a plane on the core 83 being the center of the base member15, and is different from the aforementioned integrated carriers 42 and62 where the base member 15 is rolled in one layer only in a cylindricalshape.

Furthermore, in the device for containing, reacting and measuring 81according to this embodiment, a cylindrical external screw section 96 isprovided beneath the mounting section 90 with a thread 98 provided on anexternal surface thereof. On the other hand, a cylindrical recess screwsection 95 is provided on an upper portion of the large diameter section94, with a screw thread 97 provided on an internal surface thereof.Moreover, an O-ring 99 is provided between the external screw section 96and the recess screw section 95 to give high water tightness.

As a result, with this embodiment, the integrated carrier 82 which has agreater diameter than the mounting section 90 can be easily accommodatedby unfastening the external screw section 96 from the recess screwsection 95. A pipe 100 of a predetermined length may be provided so asto protrude from the lower side of the external screw section 96 toprevent lifting of the integrated carrier 82, and enable the integratedcarrier 82 to be accommodated and fixed in a predetermined position.

Furthermore, instead of the case where, as described above, the largediameter section and the mounting section are provided so as to be ableto be opened and closed by means of the screw sections so that the basemember (or the DNA chip or the integrated carrier) is provided so as tobe able to be accommodated or taken out, after accommodating the basemember in the large diameter section, this may be sealed in by weldingwith ultrasonic welding or the like between the mounting section and thelarge diameter section. In this case, since from the start the basemember is accommodated inside the container section, then the reliableprevention of cross-contamination is possible.

The above described respective embodiments have been described in detailto further explain the present invention, and in no way preclude otherembodiments. Consequently the embodiments can be altered provided thegist of the invention is retained. For example, with each of theembodiments, the description was only for the case whereoligonucleotides were used as the detection substance. However theinvention is not limited to this case, and for example not only othergenetic material but also immunity substances, amino acids, proteins,sugars and so forth may be used. Furthermore, in the first embodiment,the description was for the case where a pump was used as the drawingand discharging section. However the invention is not limited to thiscase, and for example this may comprise a cylinder and piston.

Moreover, in the above description, the case where fluorescence wasmeasured as the measurement device was described. However the case ofchemiluminescence, or measurement of electromagnetic waves of variouswavelengths is also possible. For example, the case of measuringwavelength ranges of electromagnetic waves of for example infrared rays,ultraviolet rays, X-rays, radio waves and so forth outside of the visuallight, as the electromagnetic waves is also possible.

Furthermore, in the above description, only the case where each pipettesection or slender tube was one set was described. However the inventionis not limited to this case, and for example a case where multiple setsof pipette sections or slender tubes are provided in rows is alsopossible. As a result, processing can be made even more efficient.Moreover, needless to say, the numerical values used in the abovedescription are only for example, and are not limiting to the invention.Furthermore, the various components constituting the device forcontaining, reacting and measuring described in the various embodimentsmay be optionally selected and suitably modified and combined to therebymake up new apparatus for containing, reacting and measuring.

1-14. (canceled)
 15. A method of containing, reacting and measuringcomprising: a containing step comprising containing a base member withvarious substances for detection having predetermined chemicalstructures fixed thereto along a longitudinal direction with each of thechemical structures associated with their fixed positions in atransparent tubular container section; said tubular container sectionhaving a diameter and a longitudinal length; a reaction step comprisingdrawing a liquid comprising one or more labeled target substances toinside said tubular container section via an inlet/outlet and immersingsaid base member in said liquid to react said one or more labeled targetsubstances with said substances for detection at the respective fixedpositions along the longitudinal direction, wherein drawing said liquidcomprises drawing said liquid by using a drawing and discharging sectionconnected to said tubular container section; a measurement preparationstep comprising removing said liquid and any target substance which hasnot contributed to the reaction from said tubular container section viathe inlet/outlet by using the drawing and discharging section; and ameasurement step comprising: effecting relative translational and/orrotational movement between the base member and a light receivingsection positioned outside of the tubular container section; irradiatinglight to the base member during effecting relative translational and/orrotational movement between the base member and the light receivingsection, comprising irradiating light to the base member via: all aroundthe perimeter of the tubular container section, and along at least aportion of the longitudinal length of the tubular container section; andmeasuring light from the respective fixed positions along thelongitudinal direction using the light receiving section duringeffecting relative translational and/or rotational movement between thebase member and the light receiving section, comprising measuring lightfrom the respective fixed positions via: all around the perimeter of thetubular container section, and along at least a portion of thelongitudinal length of the tubular container section.
 16. A method ofcontaining, reacting and measuring according to claim 15, wherein insaid measurement preparation step there is included a step for drawingmeasurement liquid after removing target substance which have notcontributed to reaction and liquid suspending these, and saidmeasurement step measures in a condition with said base member immersedin measurement liquid.
 17. A method of containing, reacting andmeasuring according to claim 15, wherein the reaction step comprises atleast one of the following: shaking the container section; anddischarging the liquid from the container section via the inlet/outletby using the drawing and discharging section and then repeating drawinga liquid comprising the labeled target substance to inside the containersection.
 18. A method of containing, reacting and measuring comprising:a containing step comprising containing a base member with varioussubstances for detection having predetermined chemical structures fixedthereto along a longitudinal direction with each of the chemicalstructures associated with their fixed positions through a containeropening in a transparent tubular container section, said tubularcontainer section having a diameter and a longitudinal length; areaction step comprising drawing a liquid comprising a labeled targetsubstance to inside said tubular container section via an inlet/outletby using a drawing and discharging section connected to the containeropening and immersing said base member in said liquid to react saidtarget substance with said substance for detection; a measurementpreparation step comprising removing said liquid and any targetsubstance which has not contributed to the reaction via the inlet/outletby using the drawing and discharging section; and a measurement stepcomprising measuring light from the base member contained in saidtubular container section in a condition associated with the fixedposition, by scanning all fixed positions of said base member by:relatively moving said tubular container section or a light receivingposition, and scanning all around the perimeter of the tubular containersection and along at least a portion of the longitudinal length of thetubular container section during relatively moving said tubularcontainer section or said light receiving position.
 19. A method ofcontaining, reacting and measuring according to claim 18, wherein insaid measurement preparation step there is included a step for drawingmeasurement liquid after removing target substances which have notcontributed to reaction and liquid suspending these, and saidmeasurement step measures in a condition with said base member immersedin measurement liquid.
 20. A method of containing, reacting andmeasuring according to claim 18, wherein in said reaction step, saidcontainer section is shaken, or drawing and discharging are repeated.21. A method of containing, reacting and measuring comprising: acontaining step comprising containing a base member of a long andslender shape, with various substances for detection havingpredetermined chemical structures fixed thereto along a longitudinaldirection with each of the chemical structures associated with theirfixed positions through a container opening in a transparent tubularcontainer section, said tubular container section having a diameter anda longitudinal length; a reaction step comprising drawing a liquidcomprising one or more labeled target substances to inside said tubularcontainer section via an inlet/outlet and immersing said base member insaid liquid to react said one or more labeled target substances withsaid substance for detection at the respective fixed positions along thelongitudinal direction, wherein drawing said liquid comprises drawingsaid liquid by using a drawing and discharging section connected to saidtubular container section; a measurement preparation step comprisingremoving said liquid and any target substance which has not contributedto the reaction from said tubular container section via the inlet/outletby using the drawing and discharging section; and a measurement step,comprising: effecting relative translational and/or rotational movementbetween the base member and a light receiving section positioned outsideof the container section; and measuring light from the respective fixedpositions along the longitudinal direction using the light receivingsection during effecting relative translational and/or rotationalmovement between the base member and the light receiving section,comprising measuring light from the respective fixed positions via: allaround the perimeter of the tubular container section, and along atleast a portion of the longitudinal length of the tubular containersection.
 22. A method of containing, reacting and measuring according toclaim 21, wherein in said measurement preparation step there is includeda step for drawing measurement liquid after removing target substanceswhich have not contributed to reaction and liquid suspending these, andsaid measurement step measures in a condition with said base memberimmersed in measurement liquid.
 23. A method containing, reacting andmeasuring according to claim 21, wherein the reaction step comprises atleast one of the following: shaking the container section; anddischarging the liquid from the container section via the inlet/outletby using the drawing, and discharging section and then repeating drawinga liquid comprising the labeled target substance to inside the containersection.